Alterations in Blood Pressure and Heart Rate Variability in Transgenic Rats With Low Brain Angiotensinogen

Baltatu, Ovidiu Constantin; Janssen, Ben J. A.; Bricca, Giampiero; Plehm, Ralph; Monti, Jan; Ganten, Detlev; Bäder, Michael

doi:10.1161/01.hyp.37.2.408

Cited by 79 publications

(66 citation statements)

References 45 publications

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“…In addition, renal denervation resulted in a significant reduction of LVI only in female SHR, although the blood pressure was similarly decreased by the maneuver in both sexes. This effect occurred without alterations in BRS and thus does not support previous studies indicating that cardiac hypertrophy is associated with an alteration in BRS (1,18). The mechanism then for the reduction in LVI with renal denervation in female SHR is not clear from the present study.…”

Section: Discussioncontrasting

confidence: 99%

Role of the renal nerves in blood pressure in male and female SHR

Iliescu

Yanes²,

Bell³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Female spontaneously hypertensive rats (SHR) have lower blood pressures than males. The renin-angiotensin system plays an important role in the sexual dimorphism of blood pressure in SHR. The sympathetic nervous system can stimulate renin release, and, therefore, the present study was performed to determine whether the renal sympathetic nerves play a role in the sexual dimorphism of blood pressure in SHR. Male and female SHR underwent bilateral kidney denervation or sham surgery, and, 2 wk later, mean arterial pressure (MAP) and pulse interval were recorded, and baroreflex sensitivity (BRS) was measured by the sequence technique. Left ventricle index (LVI) was also calculated. MAP was higher in sham-operated males than females (182 Ϯ 5 vs. 169 Ϯ 4 mmHg; P Ͻ 0.01), but, despite the higher MAP in males, LVI was significantly greater in female rats. BRS was not different between sham-operated male and female SHR. Following bilateral renal denervation, MAP was decreased by a similar percentage (8 -10%) in males (169 Ϯ 2 mmHg) and females (152 Ϯ 3 mmHg), whereas LVI was reduced only in female SHR. BRS was not altered by renal denervation in either sex. These data indicate that renal nerves play a role in the control of blood pressure in SHR independent of sex, but do not play a role in mediating the sex differences in blood pressure. baroreflex sensitivity; mean arterial pressure; sexual dimorphism; renal denervation ACCUMULATING EVIDENCE SUGGESTS that men are at greater risk for cardiovascular disease than are age-matched, premenopausal women. Also, the incidence and severity of hypertension, a major risk factor for cardiovascular disease, are lower in women than in men (19). The mechanisms responsible for sex differences in blood pressure in men and women are not clear, but indexes of sympathetic nerve activity appear to be lower in women compared with men (14), and this could contribute to sex differences in blood pressure control (7).As found in human studies, we have previously shown that, in the spontaneously hypertensive rats (SHR), males have higher blood pressure than females (17). We have also shown that the renin-angiotensin system (RAS) plays a role in the sex differences in blood pressure in SHR (17). Converting enzyme inhibition normalizes blood pressure in all SHR, regardless of sex, but also mediates the 25-to 30-mmHg difference in blood pressure between males and females. In addition, androgens are incapable of increasing blood pressure if the RAS is blocked. Extensive evidence points to the renal nerves as a link between the sympathetic nervous system and long-term blood pressure control by the kidneys (8). Activation of the renal nerves stimulates renin release (9). Other investigators have shown that the male SHR has increased sympathetic outflow (3, 20) and renal sympathetic nerve activity compared with normotensive rats (4). Furthermore, renal denervation attenuates hypertension in male SHR (23). However, there have been no studies in which the role of the renal sympathetic nerves in mediating t...

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Section: Discussioncontrasting

confidence: 99%

Role of the renal nerves in blood pressure in male and female SHR

Iliescu

Yanes²,

Bell³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Although increased baroreflex sensitivity was reported in some studies (2,4), another study reported no change in baroreceptor reflex in rats lacking glial AGT (7). An alteration in circadian variation in blood pressure was also reported in these rats (1). The data obtained to date therefore support the conclusion that glial cells are an essential source of ANG II substrate in the brain in the regulation of cardiovascular function.…”

Section: Discussionsupporting

confidence: 82%

Glial-specific ablation of angiotensinogen lowers arterial pressure in renin and angiotensinogen transgenic mice

Sherrod¹,

Davis²,

Zhou³

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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-Angiotensinogen (AGT) is mainly expressed in glial cells in close proximity to renin-expressing neurons in the brain. We previously reported that glial-specific overexpression of ANG II results in mild hypertension. Here, we tested the hypothesis that glial-derived AGT plays an important role in blood pressure regulation in hypertensive mice carrying human renin (hREN) and human AGT transgenes under the control of their own endogenous promoters. To perform a glial-specific deletion of AGT, we used an AGT transgene containing loxP sites (hAGT flox ), so the gene can be permanently ablated in the presence of cre-recombinase expression, driven by the glial fibrillary acidic protein (GFAP) promoter. Triple transgenic mice (RAC) containing a: 1) systemically expressed hREN transgene, 2) systemically expressed hAGT flox transgene, and 3) GFAP-cre-recombinase were generated and compared with double transgenic mice (RA) lacking cre-recombinase. Liver and kidney hAGT mRNA levels were unaltered in RAC and RA mice, as was the level of hAGT in the systemic circulation, consistent with the absence of cre-recombinase expression in those tissues. Whereas hAGT mRNA was present in the brain of RA mice (lacking cre-recombinase), it was absent from the brain of RAC mice expressing crerecombinase, confirming brain-specific elimination of AGT. Immunohistochemistry revealed a loss of AGT immunostaining glial cells throughout the brain in RAC mice. Arterial pressure measured by radiotelemetry was significantly lower in RAC than RA mice and unchanged from nontransgenic control mice. These data suggest that there is a major contribution of glial-AGT to the hypertensive state in mice carrying systemically expressed hREN and hAGT genes and confirm the importance of a glial source of ANG II substrate in the brain.renin-angiotensin system; glia; brain; hypertension DIRECT INJECTION OF ANG II into the brain can cause a rise in systemic blood pressure because of its ability to increase sympathetic outflow and vasopressin release (43). Brain ANG II can also cause long-term increases in arterial pressure through its dipsogenic effects. The importance of the endogenous local production and action of ANG II is supported by experiments directly injecting inhibitors, antagonists, and antisense oligonucleotides directed against the renin-angiotensin system (RAS) into the brain (11,27). Moreover, increased activity of the brain RAS has been implicated as a mechanism causing and maintaining hypertension in both genetic and experimental models (11,13,28,32). Despite overwhelming evidence supporting a cardiovascular role for brain ANG II, the precise mechanisms for its local synthesis in the brain remain unclear. Uncertainties that need to be resolved include identifying the precise cellular and regional production of local ANG II and its relationship to ANG II receptor-containing cells in cardiovascular control regions and the relative importance of circulating and locally produced ANG II in circumventricular organs vs. that locally produced inside th...

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“…Frequently, so-called HRV analysis in animals is performed on data derived not from an ECG signal but from the arterial pulse waveform obtained by a radiotelemetry implanted into a main artery (3,4,19). This is a much different pulse wave monitoring technique than has been investigated in clinical studies, and it is thus important to understand how well measures of pulse rate variability (PRV) obtained via chronically implanted radiotelemetry agree with measures of HRV obtained via ECG.…”

mentioning

confidence: 99%

Validation of pulse rate variability as a surrogate for heart rate variability in chronically instrumented rabbits

Pellegrino

Schiller

Zucker

2014

American Journal of Physiology-Heart and Circulatory Physiology

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Pellegrino PR, Schiller AM, Zucker IH. Validation of pulse rate variability as a surrogate for heart rate variability in chronically instrumented rabbits. Am J Physiol Heart Circ Physiol 307: H97-H109, 2014. First published May 2, 2014; doi:10.1152/ajpheart.00898.2013.-Heart rate variability (HRV) is a function of cardiac autonomic tone that is widely used in both clinical and animal studies. In preclinical studies, HRV measures are frequently derived using the arterial pulse waveform from an implanted pressure telemetry device, termed pulse rate variability (PRV), instead of the electrocardiogram signal in accordance with clinical guidelines. The acceptability of PRV as a surrogate for HRV in instrumented animals is unknown. Using rabbits implanted with intracardiac leads and chronically implanted pressure transducers, we investigated the correlation and agreement of timedomain, frequency-domain, and nonlinear indexes of HRV and PRV at baseline. We also investigated the effects of ventricular pacing and autonomic blockade on both measures. At baseline, HRV and PRV time-and frequency-domain parameters showed robust correlations and moderate to high agreement, whereas nonlinear parameters showed slightly weaker correlations and varied agreement. Ventricular pacing almost completely eliminated HRV, and spectral analysis of the PRV signal revealed a HRV-independent rhythm. After cardiac autonomic blockade with atropine or metoprolol, the changes in timeand non-normalized frequency-domain measures of PRV continued to show strong correlations and moderate to high agreement with corresponding changes in HRV measures. Blockade-induced changes in nonlinear PRV indexes correlated poorly with HRV changes and showed weak agreement. These results suggest that time-and frequency-domain measures of PRV are acceptable surrogates for HRV even in the context of changing cardiac autonomic tone, but caution should be used when nonlinear measures are a primary end point or when HRV is very low as HRV-independent rhythms may predominate.heart rate variability; pulse rate variability; pulse interval; sympathovagal balance

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Alterations in Blood Pressure and Heart Rate Variability in Transgenic Rats With Low Brain Angiotensinogen

Cited by 79 publications

References 45 publications

Role of the renal nerves in blood pressure in male and female SHR

Role of the renal nerves in blood pressure in male and female SHR

Glial-specific ablation of angiotensinogen lowers arterial pressure in renin and angiotensinogen transgenic mice

Validation of pulse rate variability as a surrogate for heart rate variability in chronically instrumented rabbits

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